Medical cannabis and cannabinoids

Does it work ?

Medical cannabis (whole plant-extracts) or isolated cannabinoids?

In appraising the evidence for the effectiveness of cannabis-based medicines, it is important to distinguish between the different preparations and substances available (i.e. different whole-plant extracts, synthetic delta-9-tetrahydrocannabinol (THC) and THC derivates, isolated cannabidiol). Evidence regarding isolated THC, for example on the high frequency of side-effects on the central nervous system, cannot be transferred directly to other cannabis-based medicines, and vice versa. As mentioned earlier, previous research has shown that cannabidiol, but also other cannabinoids, may reduce undesirable effects on the central nervous system (both psychoactive and anxiogenic), as well as on the cardiac system; they may also contribute other therapeutic effects.12,14 It seems that these facts should be taken into consideration when exploring the full potential of cannabis-based medicines; research should not focus solely on THC (or other isolated substances).12,14,15,20

1. Do cannabis-based medicines work for nausea and emesis in cancer patients?

Nausea and emesis induced by chemotherapy

Systematic reviews

A systematic review, and also a meta-analysis, are available establishing the efficacy of cannabis-based medicines against acute chemotherapy-induced nausea and vomiting (CINV).21,22 The meta-analysis included trials investigating oral dronabinol (30–40 mg), oral nabilone and intramuscular levonantradol compared with placebo and with antiemetics available in the 1980s (prochlorperazine, metoclopramide, haloperidol, domperidone and others). Dronabinol (but not nabilone and levonantradol) showed significantly better control (in terms of remission) of acute CINV than the control medication in medium emetogenic chemotherapies, but side-effects occurred more often (dizziness, hallucinations, dysphoria, hypotension). The cannabinoids were preferred for future chemotherapy cycles by the majority of patients in crossover trials. Since all included trials were done before the development of modern forms of antiemetic prophylaxis (5-HT3 antagonists, NK1-receptor antagonists and drug combinations including glucocorticoids), no statement about the potential benefit of the investigated cannabis-based medicines, as compared to or in addition to these modern forms, could be made by the authors. They concluded that, owing to other mechanisms of action, benefiting from cannabis-based medicines in the new era of antiemetics is still plausible (e.g. as add-on medication for patient with refractory nausea) but needs further research.

A systematic review on antiemetic medication for the prevention and treatment of CINV in children identified four randomised controlled trials investigating cannabis-based medicines, which were not meta-analysed because of study heterogeneity.23 The authors concluded that cannabis-based medicines ‘are probably effective but produce high levels of side effects’ and no clear route, schedule or dose recommendation could be identified from the included studies.

Controlled trials

Table 1 summarises the results of controlled clinical trials for CINV. One randomised, placebo-controlled trial investigated the efficacy of dronabinol alone or when combined with ondansetron for the prevention of delayed CINV.24 Sixty-four participants receiving moderate to high emetogenic chemotherapy were randomised to one of four intervention groups. All participants received dexamethasone plus ondansetron before chemotherapy, the three active intervention groups received additional dronabinol on the day of chemotherapy and either dronabinol (individual dose titration), ondansetron or both on the following four days after chemotherapy. The primary endpoint total response was not different between placebo and all the active groups. Dronabinol and ondansetron were equally effective as were the combination of both for the total control of nausea and the intensity of nausea on a visual analogue scale (secondary endpoints). Acute CINV on the first day of chemotherapy was reduced in the three groups receiving additive dronabinol compared to the standard treatment alone (dexamethasone + ondansetron). The incidence of adverse events was not different in the active groups, which the authors hypothesise might be because of the lower dose of THC (maximum 20 mg) than in the studies included in the above-mentioned meta-analysis (30-40 mg).22 However, this trial failed to recruit the necessary number of participants for a valid evaluation and findings need to be replicated in a larger study to further elucidate the potential benefits of additive dronabinol.

Another randomised controlled trial, this time a pilot phase II trial, tested the whole-plant extract preparation nabiximols (individual dose titration), against placebo, as an add-on to standard prophylaxis (not defined, but mostly dexamethasone and 5-HT-3-antagonists) and treatment of delayed CINV.25 In all, 16 patients receiving moderately emetogenic chemotherapy, that had experienced delayed CINV despite standard prophylaxis in the previous chemotherapy cycle, were included. They were advised to administer a maximal dose, defined by toxicity, until 2 hours after the application of the chemotherapy, and thereafter if nausea occurred, until day 4 after administration of the chemotherapy. Cancer types were not equally distributed in the two groups. The primary endpoint total remission was significantly more often observed in the nabiximols group. More mild or moderate neuropsychiatric adverse events were experienced in the nabiximols group. Further larger studies with fully defined standard CINV prophylaxis and equally distributed populations are needed to confirm this findings.

Nausea and emesis induced by radiotherapy

One double-blind randomised crossover trial compared the THC derivate nabilone and metoclopramide for the prevention of radiotherapy-induced nausea in 40 patients.26 Findings suggested no difference in the antiemetic effect of 2 mg nabilone compared to 30 mg metoclopramide, but more patients in the nabilone group had adverse reactions (dizziness, disorientation, dry mouth, fatigue).

Multifactorial nausea and emesis in advanced cancer patients

For multifactorial nausea and vomiting that often occurs in patients with advanced incurable cancer (‘palliative care patients’), only case reports and one uncontrolled observational study have been published.27 Over the course of 30 days, 112 advanced cancer patients were observed in a specialist palliative care centre, 47 receiving nabilone, 65 not. Propensity-score adjusted improvement of nausea (and pain) was significantly better in the patients receiving nabilone. No information on safety is available. Owing to the fact that the patients were not randomised, no causality can be inferred from this study.

In conclusion, isolated THC seems to be more effective, but also have more side-effects, than ‘old’ standard antiemetics. Only one underpowered study25 has compared isolated THC directly with a 5-HT3-anagonist showing no difference between the groups - a result, however, that needs confirmation. There might be a clinical potential for the use of cannabis-based medicine as add-on therapy for patients with refractory CINV, despite modern antiemetics, but more research is needed to confirm this indication.

The Cannabis-In-Cachexia-Study-Group et al. conducted a randomised placebo-controlled phase III trial comparing oral THC with an oral cannabis extract and placebo for patients with cancer cachexia-related anorexia.29 In all, 243 adults with advanced cancer were randomly assigned to the cannabis extract, THC alone or placebo orally daily for 6 weeks. The results showed no benefit of cannabis-based medicines over placebo on appetite or overall quality of life (primary study end points), or mood or nausea (secondary end points). Cannabis extract and THC was well tolerated. Recruitment for this study was terminated early because of insufficient differences between study arms.

Brisbois et al. investigated THC (individual dose titration) or placebo in a randomised pilot trial in 46 patients with advanced cancer with altered taste and smell (chemosensory) perceptions, which are common in patients with cancer cachexia.30 Per-protocol analyses of 21 patients found increased appetite and improved taste perception in the THC group; THC was well tolerated. These findings need to be confirmed in a larger study.

In conclusion, based on these studies, the clinical potential of cannabis-based medicines for symptoms associated with cancer cachexia is still unclear.

Doses were fixed except in the most recent study,30 where individual dose titration was used. This approach was also successfully used in the newer promising studies on CINV25 and pain.20,31 Incidentally, the dosage of 5-7.5 mg for THC seems rather low. It was probably chosen because of concerns about potential dose-dependent severe adverse effects, which seem not have been a major problem in the above-mentioned studies for the other indications using a whole-plant based preparation in individual dose titration.

It is important to note that stages of cachexia were heterogeneous in both earlier trials because, at the time when the studies were undertaken, the different stages of cachexia had not yet been defined.32 This diversity might have affected outcomes, since response to treatments mostly depend which stage of cachexia has been reached.32

3. Do cannabis-based medicines work for pain in patients with cancer?

Systematic reviews

A systematic review of randomised clinical trials has investigated the efficacy of cannabis-based medicines in the management of pain (cancer pain, chronic non-cancer pain and postoperative pain).33 The five studies on cancer pain included a total of 128 cancer patients comparing oral THC, nabilone, levonantradol or a THC congener (benzopyranopyridine) to placebo, codeine or a barbiturate. The pain syndromes were not further classified. The first three cannabinoids investigated were found to be more effective than placebo, and as effective as codeine (dose for THC: 5-20 mg). Studies were rather small (n=10-37) and dose-limiting adverse effects were common. Reviewers concluded that there is insufficient evidence to support the introduction of cannabis-based medicines for widespread clinical use as analgesics.

Clinical studies

Table 3 summarises results from controlled clinical trials of cannabis-based medicines for cancer pain. Johnson et al. conducted a randomised controlled trial comparing two cannabis extracts (nabiximols and a THC-rich whole-plant extract, individual dose titration) versus placebo for pain control on top of opioids in 177 patients with cancer pain insufficiently relieved by opioids.31 Pain syndromes, as well as previous cannabis experience, were variable but equally distributed between the groups. A significant improvement in average pain as compared to baseline was seen for nabiximols compared to the THC-rich extract and placebo. Mild to moderate adverse events (somnolence, dizziness, confusion) were seen in both active groups. This trial was followed by an open-label extension study with some of the study patients to evaluate long-term efficacy and tolerability.34

Portenoy et al. conducted a randomised controlled trial comparing three dose ranges of nabiximols and placebo in 360 patients with cancer pain insufficiently relieved by opioids.20 Pain syndromes were classified, but not equally distributed between the groups. Previous cannabis experience was more frequent in the active groups than in the placebo group (which could have affected blinding). The proportion of responders (reduction of average pain score per day) was significantly higher in the lower- and middle-dose groups compared to placebo, but not in the high-dose group. Only the high-dose group had significantly more adverse events than placebo.

Lynch et al. compared nabiximols (individual dose titration) versus placebo in 18 patients with chemotherapy-induced neuropathic pain in a pilot crossover randomised controlled trial.35 The analysis of the whole group showed no statistically significant difference between active treatment and placebo. Five of the patients, however, were considered as responders (two or more points reduction in the numeric rating scale) from which the authors concluded that further research is warranted. Nabiximols was well tolerated and, in the extension phase with 10 patients, some reported further improvement of pain.

In conclusion, medical cannabis seems to have clinical potential for a variety of cancer pain mechanisms insufficiently relieved by opioids. However, more high-quality research on pain syndrome specific indications and optimal (individual) doses are needed to define the role of cannabis-based medicines for the treatment of cancer patients with pain.

Legal notice
The present documentation has been compiled by the CAM-CANCER Project with all due care and expert knowledge. However, the CAM-CANCER Project provides no assurance, guarantee or promise with regard to the correctness, accuracy, up-to-date status or completeness of the information it contains. This information is designed for health professionals. Readers are strongly advised to discuss the information with their physician. Accordingly, the CAM-CANCER Project shall not be liable for damage or loss caused because anyone relies on the information.